S-carboxymethylmercapto-g-



United States Patent S-CARBOXYMETHYLMERCAPTO-fi- AMINOURACILS Ehner F.Schroeder, Chicago, Ill., assignor to G. D. Searle & Co., Chicago, 111.,a corporation of Delaware This invention relates to5-carboxymethylmercapto-6- aminouracils of the following structureon-cm-ooon NH: N

wherein R is a member of the group of radicals consisting of loweralkyl, lower alkenyl, and hydroxy(lower) alkyl; and n is an integer from0 to 2 inclusive.

The compounds of the invention are prepared from appropriately1,3-disnbstituted-5-halo-6-aminouracils by reacting the latter. withthioglycolic acid or an ester thereof. The reaction is preferablycarried out in alkaline solution at elevated temperatures, i.e. about100 and for a period of time adequate for the reaction, i.e. from aboutone-half hour to about an hour. The alkaline metal hydroxides oralkaline earth hydroxides can be used to make the reaction mediumalkaline. The product can be isolated by acidifying the reactionmixture, recovering the precipitated product and purifying the crudeproduct thus obtained by redissolving it in aqueous alkaline solutionand reprecipitating with acid.

The halogen present in the S-halogenated uracils used as startingmaterials is preferably chlorine.

Other compounds of the invention in which the sulfur atom is oxidized toa sulfinyl or a sulfonyl group are obtained from the correspondingcarboxymethylmercaptouracils by oxidation of the latter, for example, byuse of a peroxyacid such as peroxyacetic acid, peroxybenzoic acid,trifiuoroperoxyacetic acid and the like. The oxidation is carried outpreferably in aqueous alkaline medium. After the oxidation step iscompleted, the reaction mixture is acidified with a mineral acid such ashydrochloric acid, sulfuric acid or the like, and the product whichprecipitates recovered. The product can be purified further byrecrystallization from a suitable solvent such as water, ethyl acetate,alcohol and the like.

The compounds of this invention are useful as a result of their valuablepharmacological properties. They are, for example, anti-inflammatoryagents as evidenced by their ability to inhibit the local edemaformation associated with inflammatory states. They possess alsobronchodilating activity.

The invention is described in greater detail in the examples whichfollow. These examples are presented by way of illustration and not oflimitation. Quantities are expressed in parts by weight. Temperaturesare expressed in degrees centigrade C.).

EXAMPLE 1 1-pr0pyl-3-ethylcarboxymethylmercapto-6-aminouracil A solutionof 6.07 parts of thioglycolic acid in 25 parts of water, previouslyadjusted to pH 7 with sodium hydroxide, is added to a suspension of 13.9parts of 1-npropy1-3-ethyl-5-chloro-6-aminouracil in a solution of 2.4parts of sodium hydroxide in 35 parts of water. The resulting mixture isheated at 100 for minutes during which time complete solution takesplace. The reaction mixture is acidified with dilute hydrochloric acidand cooled. The oily precipitate which separates is stirred and allowedto stand until solidified. It is then collected by filtration and washedwith water. Further purification is effected by dissolution in 125 partsof water containing 2.5 parts of sodium hydroxide, decolorization withactivated carbon, and acidification with hydrochloric acid. The solidwhich separates is collected on a filter, washed with water, and driedat 80 to yield 1-propyl-3-ethyl-5- carboxymethylmercapto-6-aminouracilmelting at 182- EXAMPLE 21,3-dimethyl-5-carboxymethylmercapto-(i-aminouracil A solution of 6.07parts of thioglycolic acid in 25 parts of water, which has beenneutralized with sodium hydroxide, is added to a suspension of 11.37parts of 1,3- dimethyl-S-chloro-6-aminouracil in a solution of 2.4 partsof sodium hydroxide in parts of water and the mixture heated for 30minutes at 100, during which time complete solution occurs. Aftercooling and acidifying with a slight excess of dilute hydrochloric acid,the crystals which appear are recovered by filtration, washed with waterand dried to yield l,3-dimethyl-5-carboxymethylmercapto-G-aminouracil ascolorless crystals melting at 218220 with etlervescence. The product isreadily soluble in dilute aqueous sodium hydroxide.

EXAMPLE 3 1-allyl-3-ethyl-5carb0xymethylmercaplo-sS-aminouracil Asuspension of 18.37 parts of 1-allyl-3-ethyl-5- chloro-6-aminouracil ina solution of 3.2 parts of sodium hydroxide and 50 parts of water istreated with a solution of 8.1 parts of thioglycolic acid in 25 parts ofwater which has been previously neutralized with sodium hydroxide. Thereaction mixture is heated for one hour at 100 during which timecomplete solution takes place. The reaction mixture is diluted withparts of water, made acid with hydrochloric acid and the precipitatewhich forms recovered by filtration. The precipitate is washed withwater and purified by dissolution in 200 parts of water containing 4parts of sodium hydroxide, decolorization with activated carbon andacidification with hydrochloric acid. A crystalline precipitate formswhich is recovered by filtration, washed and dried at to yield1-allyl-3-ethyl-5-carboxymethylmercapto-6-an1inouracil, M.P. 176-177.

Substitution of an equal amount of 1 methallyl-3-methyl-S-chloro-6-arninouracil for the 1-allyl-3-ethyl-5-chloro-6-aminouracil used in the foregoing procedure yields1-methallyl-3-methyl5-carboxymethylmercapto-6- aminouracil.

EXAMPLE 4 1,3-di-n-butyl-5-carboxymethylmercapto-6-aminouracil Asolution of 8.1 parts of thioglycolic acid in 35 parts of water,previously neutralized with sodium hydroxide, is added to a suspensionof 21.9 parts of 1.3- di-n-butyl-S-chloro-6-arninouracil in 50 parts ofwater containing 3.2 parts of sodium hydroxide. The reaction mixture isheated at for one hour, cooled, made acid with a slight excess ofhydrochloric acid, and the oily precipitate which forms stirred andallowed to stand until solidified. The solid thus obtained is recoveredby filtration, washed with water and purified by dissolution in 200parts of water containing 4 parts of sodium hydroxide. The alkalinesolution is decolorized with activated carbon, filtered and acidifiedwith hydrochloric acid. The oily precipitate is stirred and chilled toinduce crystallization, triturated with water and dried at 80 to yield1,3-di-n-butyl-5-carboxymethylmercapto-6-aminouracil which melts at 157-159 with prior softening at 155.

EXAMPLE 5 1 2 -hydroxyethyl -3-ethyl-5 -carbxym'ethylmercapt0=6-amin0uracil A suspension of 14 parts of 1-(2-l1ydroxyethyl)3-ethyl-S-chloro-6-aminouracil in 35 parts of water containing 2.4 partsof sodium hydroxide is treated with a solution of 6 parts ofthioglycolic acid in 15 parts of water which has been previouslyneutralized with sodium hydroxide. The reaction mixture is heated at 100for one hour, cooled, made acid with hydrochloric acid and chilled forseveral hours. The crystalline material thus obtained is recovered byfiltration, washed with water and recrystallized from water solution toyield 1 (Z-hydroxyethyl)-3-ethyl-S-carboxymethylmercapto-6-aminouracilwhich melts at 206-207".

Substitution of 14 parts of 1-(3-hydroxypropyD-3- methyl 5 chloro- 6aminouracil for the hydroxyethyl derivative as a starting material inthe foregoing procedure yields1-(3-hydroxypropyl)-3-methyl-5-carboxymethylmercapto-6-aminouracil.

EXAMPLE 6 1 -n p1'opyl-3- ethyZ-S-carboxymethylsulfinyl-6-aminouracil Toa cold solution of 14.53 parts of l-n-propyl-3-ethyl-S-carboxymethylmercapto-6-an1inouracil and 7 parts of sodiumhydroxide in 100 parts of water is added 59.3 parts of a cold solutionprepared by dilution of 9.3 parts of 40% peracetic acid in glacialacetic acid with 50 parts of water. The reaction mixture is allowed tostand for 15 minutes, filtered, and made acid by addition of 25 parts ofconcentrated hydrochloric acid. The acidified mixture is chilled and thecrystals which separate are filtered off, washed with water, dried andrecrystallized from ethyl acetate to yield l-n-propyl-3-ethyl-5-carboxymethylsulfinyl-6-aminouracil as colorless crystalswhich melt at 146-147 (with decomposition).

4 EXAMPLE 7 1 -n-pr0py l-3-ethy l-5 -ca'rb oxymethylsulfonyl-6-aminouracil A cold solution of 41.4 parts of 40% peraceticacid in glacial acetic acid diluted with parts of water is added to acold solution of 27.4 parts of 1-n-propyl-3-ethyl-5-carboxymethylmercapto-6-aminouracil in 250 parts of watercontaining 24 parts of sodium hydroxide. The reaction mixture is allowedto stand an additional 30 minutes after completion of the addition andthen is made strongly acid with 47.2 parts of concentrated hydrochloricacid. On cooling a precipitate forms which is recovered by filtrationand washed with water. Further purification is eifected by dissolutionin 250 parts of water containing 4 parts of sodium hydroxide,decolorization with activated carbon and acidification with 12 parts ofconcentrated hydrochloric acid. The voluminous precipitate which formsis filtered ofi, washed with water and dried to yield1-npropyl-3-ethyl-5-carboxymethylsulfonyl-6-aminouracil which melts at207 208.

What is claimed is:

1. A compound of the formula wherein R is a member of the group ofradicals consisting of lower alkyl, lower alkenyl, and hydroxy(lower)-alkyl, and n is an integer from 0 to 2 inclusive.

2. 1-n-propy1-3-ethyl-S-carboxymethylmercapto-6-ami nouracil.

3. 1,3-dirnethyl-5-carboxymethylmercapto-6-aminouracil.

4. 1-allyl-3-ethyl 5 carboxymethylmercapto- 6 aminouracil.

5. 1,3-di-n-butyl-5-carboxymethylmercapto-G-aminouracl].

6. 1-(2-hydroxyethyl) -3-ethyl-5-carboxymethylmercap to-6-aminouracil.

7, 1-n-propyl-3-ethyl-5-carboxymethylsulfinyl-6-aminouracil.

8. 1-n-propyl-3-ethyl-S-carboxymethylsulfonyl-6-amino uracil.

No references cited.

1. A COMPOUND OF THE FORMULA